Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person retains high blood sugar for a long period of time, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced, or for both reasons. Insulin is a hormone, produced in the beta cells of the pancreas, which causes cells to take up glucose from the blood, using it as an energy source. When insulin does not work properly in the body, the uptake of glucose from the blood to, for example, muscle cells becomes poor, resulting in the accumulation of glucose in the blood and the excretion of sugar in the urine. Continuance of such hyperglycemia for a long period of time causes various complications in the nerves, the kidney, the eye and the heart. Serious complications include lower limb amputation, cardiovascular disease, renal failure, retinal damage, hypertension and myocardial infarction.
Diabetes is one of the major causes of death among adults throughout the world. The number of diabetics has drastically increased along with the increase in the obese population. As of 2010, approximately 360 million people worldwide have diabetes, and the expectation is for approximately 560 million people to have diabetes in 2030.
There are two main types of diabetes. Type 1 diabetes mellitus (also known as insulin-dependent diabetes mellitus) is a chronic autoimmune disease characterized by the extensive loss of the insulin-producing beta cells of the islets of Langerhans in the pancreas (hereinafter referred to as “pancreatic islet cells” or more simply as “islet cells”). As these cells are progressively destroyed, the amount of secreted insulin decreases, the production of insulin decreases finally below the level required for euglycemia, eventually leading to hyperglycemia. Although the exact trigger for this immune response is not known, type 1 diabetes is mainly attributed to autoimmune, genetic and environmental factors. The onset of type 1 diabetes most often occurs before the age of 30. Patients with Type I diabetes have a high level of antibodies to pancreatic beta cells (hereinafter referred to as “beta cells”). However, not all patients with high levels of these antibodies develop type 1 diabetes.
Type II diabetes mellitus (also known as non-insulin-dependent diabetes mellitus) develops when muscle, fat and liver cells fail to respond normally to insulin. This response failure (known as insulin resistance) may be attributed to a decreased number of insulin receptors on these cells, or the dysfunction of the signaling pathway within the cells, or both of these factors. Initially, beta cells increase insulin output to compensate for the insulin resistance. Over time, these cells become unable to produce enough insulin to maintain normal blood glucose levels, resulting in the progression of Type II diabetes (see [Kahn B B, Cell 92:593-596, 1998]; [Cavaghan M K, et al., J. Clin. Invest. 106:329-333, 2000]; [Saltiel A R, Cell 104:517-529, 2001]; [Prentki M and Nolan C J. J Clin Invest. 116:1802-1812. (2006)]; and [Kahn S E. J. Clin. Endicrinol. Metab. 86:4047-4058, 2001]). Fasting hyperglycemia featuring Type II diabetes results from the combination of insulin resistance and beta cell dysfunction (see [UKPDS group, JAMA 281:2005-2012, 1999]; [Levy J, et al., Diabetes Med. 15:290-296, 1998]; and [Zhou Y P, et al., J. Biol. Chem. 278:51316-23, 2003]). Type II diabetes is primarily related to lifestyle factors and genetics. Among the lifestyle factors are obesity, stress, drinking, smoking, frequent pregnancy, and intemperance.
The beta cell defect has two components: the first component, an elevation of basal insulin release (occurring in the presence of low, non-stimulatory glucose concentrations), is observed in obese, insulin-resistant pre-diabetic stages as well as in Type II diabetes. The second component is a failure to increase insulin release above the already elevated basal output in response to a hyperglycemic challenge. This lesion is absent in pre-diabetes and appears to define the transition from normo-glycemic insulin-resistant states to frank diabetes. There is currently no cure for diabetes. Conventional treatments for diabetes are very limited and are focused on attempting to control the blood glucose level in order to minimize or delay complications. Current treatments target either insulin resistance (metformin, thiazolidinediones (“TZDs”)), or insulin release from the beta cell (sulphonylureas, exenatide). Sulphonylureas, and other compounds that act by depolarizing the beta cell, have the side effect of hypoglycemia since they cause insulin secretion independent of circulating glucose levels. One approved drug, Byetta (exenatide) stimulates insulin secretion only in the presence of high glucose, but is not orally available and must be injected. Januvia (sitagliptin) is another recently approved drug that increases blood level of incretin hormones, which can increase insulin secretion, reduce glucagon secretion and have other less well-known characterized effects. However, the use of Januvia is restricted in patients with renal problems. Further, Januvia and other dipeptidyl peptidases IV inhibitors may also influence the tissue levels of other hormones and peptides, and the long-term consequences of this broader effect have not been fully investigated. There is an unmet need for oral drugs that stimulate insulin secretion in a glucose dependent manner.
The elevation of beta cell cAMP (cyclic adenosine monophosphate) has a substantial potentiating effect on insulin secretion in the presence of stimulatory levels of glucose (see below). Unfortunately, many potentiators of glucose-stimulated insulin secretion also have effects outside of the islet which limit their use as diabetes therapeutics. For example, the best available selective muscarinic agonists which stimulate insulin secretion also stimulate multiple undesirable responses in multiple tissues (see [Rhoades R A and Tanner G A, eds (2003) Medical Physiology, 2nd ed Lippmcott, Williams and Wilkins. ISBN 0-7817-1936-4]). Likewise, VIP and PACAP receptors are present in multiple organ systems and mediate effects on the reproductive, immune and other diverse systems that make them less attractive as specific enhancers of glucose dependent insulin secretion.
Incretin hormones such as Glucagon-Like Peptide 1 (GLP-1) and Glucose-dependent Insulinotropic Polypeptide ([0011] GIP, also known as Gastric Inhibitory Polypeptide) also bind to specific G alpha s-coupled GPCR receptors on the surface of islet cells, including beta cells, and increase intracellular cAMP (see [Drucker D J, J. Clin. Invest. 2007 January; 117(1):24-32]). Although the receptors for these hormones are present in other cells and tissues, the overall sum of effects of these peptides appears to be beneficial at controlling the glucose metabolism in the organism (see [Hansotia T, et al., J. Clin. Invest. 2007 January; 117(1):143-52. Epub 2006 Dec. 21]). GIP and GLP-1 are produced and secreted from intestinal K and L cells, respectively, and these peptide hormones are released in response to meals by both direct action of nutrients in the gut lumen and neural stimulation resulting from food ingestion. GIP and GLP-1 have short half-lives in circulation in the human body due to the action of the protease dipeptidyl-peptidase IV (DPP-IV), and inhibitors of this protease can lower blood glucose thanks to their ability to raise the levels of active forms of the incretin peptides. The glucose lowering that can be obtained with DPP-IV inhibitors, however, is somewhat limited since these drugs are dependent on the endogenous release of the incretin hormones. Peptides (e.g., exenatide (Byetta)) and peptide-conjugates that bind to the GIP or GLP-1 receptors but are resistant to serum protease cleavage can also lower blood glucose substantially (see [Gonzalez C, et al., Expert Opin Investig Drugs 2006 August; 15(8):887-95]), but these incretin mimetics must be injected and tend to induce a high rate of nausea and therefore are not ideal therapies for general use in the Type II diabetic population. The clinical success of DPP4 inhibitors and incretin mimetics, although far from ideal, points to the potential utility of compounds that increase incretin activity in the blood or directly stimulate cAMP in the beta cell. Some studies have indicated that beta cell responsiveness to GIP is diminished in Type II diabetes (see [Nauck M A, et al., J. Clin. Invest. 91:301-307 (1993)]; and [Elahi D, et al., Regul. Pept. 51:63-74 (1994)]). Restoration of this responsiveness (see [Meneilly G S, et al., Diabetes Care. 1993 January; 16(1):110-4]) may be a promising way to improve beta cell functioning in vivo.
Since increased incretin activity has a positive effect on glucose dependent insulin secretion and other mechanisms that lead to lower blood glucose, interest is also being shown in the exploration of therapeutic approaches to increasing incretin release from intestinal K and L cells. GLP-1 secretion appears to be attenuated in Type II diabetes (see [Vilsboll T, et al., Diabetes 50:609-613]), so that an improvement in incretin release may ameliorate this component of metabolic dysregulation. Nutrients such as glucose and fat in the gut lumen prompt incretin secretion by interaction with apical receptors (see [Vilsboll T, et al., Diabetes 50:609-613]). GLP-1 and GIP release can also result from neural stimulation; acetylcholine and GRP can enhance incretin release in a manner perhaps analogous to the effects of these neurotransmitters on the beta cell in regard to insulin secretion (see ([Brubaker P, Ann N Y Acad. Sci. 2006 July; 1070:10-26]; and [Reimann F, et al., Diabetes 2006 December; 55 (Suppl 2):S78-S85]). Somatostatin, leptin and free fatty acids also appear to modulate incretin secretion (see [Brubaker P, Ann N Y Acad. Sci. 2006 July; 1070: 10-26]; and [Reimann, F. et al., Diabetes. 2006 December; 55(Suppl 2):S78-S85]). However, there does not appear to be a way to selectively impact these pathways to promote incretin secretion for therapeutic benefit.
Many people with diabetes mellitus are obese and they weigh approximately 20% more than the recommended weight for their height and build. Furthermore, obesity is characterized by hyperinsulinemia, insulin resistance, hypertension and atherosclerosis.
Obesity and diabetes are among the most common human health problems in industrialized societies. In industrialized countries a third of the population is at least 20% overweight. As of 2010, the number of obese people amounts to 470 million worldwide, and tends to increase in number every year. Obesity is one of the most important risk factors for diabetes mellitus. Definitions of obesity differ, but as a rule, a subject weighing at least 20% more than the recommended weight for his/her height and build is considered obese. The risk of developing diabetes mellitus is tripled in subjects 30% overweight, and three-quarters of those with diabetes are overweight.
Obesity, which is the result of an imbalance between caloric intake and energy expenditure, is highly correlated with insulin resistance and diabetes in experimental animals and human. However, the molecular mechanisms that are involved in obesity-diabetes syndromes are unclear. During early development of obesity, increased insulin secretion balances insulin resistance and protects patients from hyperglycemia (see [Le Stunff, et al. Diabetes 43, 696-702 (1989)]). However, after several decades, β cell function deteriorates and non-insulin-dependent diabetes develops in about 20% of the obese population (see [Pederson, P. Diab. Metab. Rev. 5, 505-509 (1989)); and (Brancati, F. L., et al., Arch. Intern. Med. 159, 957-963 (1999)). Given its high prevalence in modern societies, obesity has thus become the leading risk factor for NIDDM (see [Hill, J. O., et al., Science 280, 1371-1374 (1998)]). However, the factors which predispose a fraction of patients to alteration of insulin secretion in response to fat accumulation remain unknown.
Whether someone is classified as overweight or obese is generally determined on the basis of their body mass index (BMI) which is calculated by dividing body weight (kg) by height squared (m2). Thus, the units of BMI are kg/m2 and it is possible to calculate the BMI range associated with a minimum mortality in each decade of life. Being overweight is defined as a BMI in the range from 25 to 30 kg/m2, and obesity as a BMI greater than 30 kg/m2 (see TABLE below).
Classification of Weight by Body Mass Index (BMI)BMIClassification<18.5Underweight18.5-24.9Normal25.0-29.9Overweight30.0-34.9Obesity (Class I)35.0-39.9Obesity (Class II)>40Extreme Obesity (Class III)
A problem with this definition is that it does not take into consideration the ratio of muscle to fat (adipose tissue). Obesity may be also defined on the basis of body fat content (25% and 30% excess in males and females, respectively). As the BMI increases there is an increased risk of death from a variety of causes that are independent of other risk factors. The most common diseases that are accompanied by obesity are cardiovascular disease (particularly hypertension), diabetes (obesity aggravates the development of diabetes), gall bladder disease (particularly cancer) and reproductive diseases. Research has shown that even a modest reduction in body weight can correspond to a significant reduction in the risk of developing coronary heart disease.
Orlistat is a representative commercially available anti-obesity agent. Orlistat (a lipase inhibitor) inhibits fat absorption directly and tends to produce a high incidence of unpleasant side-effects such as diarrhea. Sibutramine (a mixed 5-HT/noradrenaline reuptake inhibitor) can increase blood pressure and heart rate in some patients. The serotonin releaser/reuptake inhibitors fenfluramine and dexfenfluramine were withdrawn due to problems in heart safety. Contrave, Lorcaserin and Qnexa failed to acquire the approval from the FDA because their use was associated with heart abnormalities and oncogenesis. Accordingly, there is a need for the development of a safer anti-obesity agent.
Obesity considerably increases the risk of developing cardiovascular diseases as well. Coronary insufficiency, atheromatous disease, and cardiac insufficiency are at the forefront of the cardiovascular complication induced by obesity. It is estimated that if the entire population had an ideal weight, the risk of coronary insufficiency would decrease by 25% and the risk of cardiac insufficiency and of cerebral vascular accidents by 35%. The incidence of coronary diseases is doubled in subjects less than 50 years of age who are 30% overweight. The diabetes patient faces a 30% reduced lifespan. After age 45, people with diabetes are about three times more likely than people without diabetes to have significant heart disease and up to five times more likely to have a stroke. These findings emphasize the relationship between risks factors for diabetes and coronary heart disease and the potential value of an integrated approach to the prevention of these conditions based on the prevention of these conditions based on the prevention of obesity (see [Perry, I. J., et al., BMJ 310, 560-564 (1995)]).
Diabetes has also been involved in the development of renal diseases, retinal diseases, and nervous-system problems. Renal disease, also called nephropathy, occurs when the kidney's “filter mechanism” is damaged and an excessive amount of protein leaks into urine leading eventually to kidney failure. Diabetes is also a main cause of damage to the retina at the back of the eye and increases the risk of cataracts and glaucoma. Finally, diabetes is associated with nerve damage, especially in the legs and feet, which interferes with the ability to sense pain and contributes to serious infections. Taken together, diabetes complications are one of the nation's leading causes of death.